Science Pool

Our popular, easy-to-follow guide: 'DDI Regulatory Guidance' is now on its 3rd edition.

Read about:

• an easy to follow summary and comparison of the latest DDI guidance from the FDA and the EMA
• a focus on reaction phenotyping, cytochrome P450 inhibition, cytochrome P450 induction, drug transporter substrate studies and drug transporter inhibition
• an overview of the regulatory methods and interpretation of data

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Our popular, easy-to-follow guide: 'Mechanisms of Drug-induced Toxicity' is available to read online.

Read about:

• an overview of the different mechanisms of toxicity including:
  
  • mitochondrial toxicity
  • reactive oxygen species (ROS) and oxidative stress
  • reactive metabolite formation
  • cell cycle mediated toxicity
  • apoptosis
  • genotoxic and non-genotoxic carcinogens
  • phospholipidosis
  • steatosis
  • cholestasis
  • cardiac ion channel effects and hypertrophy
• an assessment of the current in vitro methods available for determining mechanistic toxicology 
• key references and further reading related to the topic

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Fasiglifam (TAK-875) is a GPR40 agonist which was developed for the treatment of type 2 diabetes. However, during Phase III clinical trials, it was withdrawn due to adverse liver effects.

In this poster, we focus on:

• deciphering the mechanism of hepatotoxicity of fasiglifam (TAK-875)
• understanding the impact of plasma protein binding and mitochondrial effects by fasiglifam using the Seahorse flux analyser platform

Read our poster to learn more about our research!

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The skin is the largest organ in the human body. It contains enzymes capable of drug metabolism.

In this presentation, we focus on:

• the physiology of the skin and an overview of skin enzymology
• the role of skin metabolism in absorption, efficacy, homeostasis, drug delivery and toxicity
• adverse reactions in the skin including the mechanism behind skin sensitisation
• in vitro methods for investigating skin metabolism

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Pharmacokinetic/pharmacodynamic (PK/PD) modelling plays an important role in drug development, especially in the case of antibiotics where the data generated is used for dose prediction up to Phase 2 clinical trials. This enables efficient study designs and identification of optimal dosing regimens that may suppress drug resistance.  

In this poster, we focus on:

• mathematical modelling of in vivo and in vitro data to generate a rational design with reduced animal requirements in order to determine the pharmacodynamic driver and magnitude of antibiotic efficacy
• optimisation of the clinical dose regimen in Phase 2 clinical trials

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LC-MS provides the analytical endpoint for most discovery ADME assays. There is a constant drive to reduce LC-MS run times whilst maintaining quality. 

In this presentation, we focus on:

• a comparison of triple quadrupole MS/MS vs TripleTOF MS
• validation data for performance of the TripleTOF MS 
• use of the TripleTOF in high throughput ADME screening including intrinsic clearance assays and soft spot analysis.

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Due to an aging population, polypharmacy is increasing. Drug-drug interactions account for 5% of UK hospital admissions, and are a particular concern for common co-meds such as statins.

In this presentation, we focus on:

• a background to drug-drug interactions (DDI)
• the use of the mechanistic static models in the prediction of transporter-mediated DDI
• a comparison of the different published models and their performance 

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Pilocarpine is a muscarinic cholinergic agonist which is used as an epilepsy model in rats. 

In this presentation, we evaluate:

• the seizurogenic response of pilocarpine in vitro in different neuronal models including rat cortical neurons, rat hippocampal neurons and a human iPSC-derived co-culture model
• the importance of maturation of the cells (DIV)
• the use of MEA for the sensitive detection of firing, bursting and synchrony of the cells

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Human-derived 3D cell-based models are more representative of in vivo cellular physiology and have improved longevity in vitro.  

In this presentation, we focus on:

• causes of drug failure in drug development
• the advances in high content screening
• developments in 3D cell-based models including organ-specific cellular models
• the prediction of tissue specific toxicities such as hepatotoxicity (DILI), cardiotoxicity, nephrotoxicity and neurotoxicity

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Mitobiogenesis (or mitochondrial biogenesis) is defined as the growth and division of pre-existing mitochondria. Drug-induced perturbations in this process can result in mitochondrial dysfunction or toxicity. 

In this presentation, we focus on:

• mechanisms involved in mitochondrial toxicity including drug-induced mitobiogenesis
• the development of a high throughput high content imaging assay for detecting drug-induced effects on mitobiogenesis
• validation of the assay using known drugs which inhibit mitochondrial DNA and protein synthesis (e.g., antibiotics, anti-viral and anticancer drugs) as well as some non-mitochondrial toxicants.

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